ABSTRACT Von Willebrand disease (VWD) is the most common congenital bleeding disorder, occurring in 1% of the population and symptomatic in 0.1%. VWD is caused by defective or deficient von Willebrand factor (VWF), a multimeric protein encoded for on chromosome 12, which results in mucosal bleeding. In women with VWD, menorrhagia is the most common symptom, occurring in 80-90% and associated with iron deficiency, reduced physical and cognitive function, anxiety, depression, and poor quality of life. Current hormonal and non- hormonal therapies are limited by ineffectiveness and intolerance, and few randomized trials are available to guide treatment. The current non-hormonal agent of choice for menorrhagia, tranexamic acid (Lysteda, TA) is limited by nausea in 50%, and hormonal therapy is ineffective in 30% and poorly tolerated in 20%. Thus, the lack of safe, effective treatment for menorrhagia in women with VWD constitutes a major public health problem. A new recombinant von Willebrand factor (Vonvendi, rVWF), with improved potency, purity, and half-life, has been shown to be safe and effective in the treatment of bleeds in individuals with VWD, and is currently under review by the FDA. However, the dose and frequency used for general bleeds do not apply to menorrhagia. In a survey and literature review of 101 women with VWD, the use of VWF, plasma-derived (pdVWF) or recombinant (rVWF), resulted in reduced menstrual blood loss in over 95% with no adverse events. Yet, the optimal dose, frequency, and acceptability of VWF, which requires intravenous administration, have not been established in women with menorrhagia. We hypothesize that intravenous recombinant von Willebrand factor (rVWF) on day 1 of bleeding is more effective than oral tranexamic acid (TA) on day 1-5 of bleeding, on each of two consecutive menstrual cycles, in reducing menorrhagia and improving quality of life, despite its higher cost and intravenous route of administration. The proposed Collaborative R01 Investigator-Initiated Multi-Site Clinical Trial, therefore, is designed in response to Funding Opportunity Announcement PAR-13-128 as a multi-center prospective, randomized, crossover Phase III clinical trial, Von Willebrand Minimize (VWDMin) Trial, the purpose of which is to evaluate if rVWF is superior to TA in reducing menorrhagia in women with VWD when given during bleeding in two consecutive menstrual cycles each over 24 weeks. The trial, with clinical coordination by the University of Pittsburgh and data coordination by Pitt?s Center for Research Healthcare Data Center (CRHC DC) is feasible as 1) the trial design has been optimized for this rare population; 2) structured interviews indicate physician and parent acceptance of the trial concept; 3) the Steering Committee indicated unanimous consensus on study drug choice and dosing; and 4) surveys indicate there are sufficient hemophilia treatment centers (HTCs) and eligible subjects to conduct the trial. The concept is high-impact as it addresses the greatest unmet healthcare need in women with VWD, and, if effective, will be practice-changing. Menorrhagia will be assessed by pictorial blood assessment chart, PBAC. Safety, tolerability and acceptability will be measured by a) frequency of menstrual cycles unresponsive to study drug or rescue, recorded in a patient diary; b) cycle severity rating; c) cycle length; and d) quality-of-life questionnaires and satisfaction survey. Response to study treatment will be compared by VWF assays and genotype.